Contaminated LVPs and the Origins of Validation 2

In late 1971, FDA began an intensive review and evaluation of LVP production because of justified concerns that not all manufacturers could ensure the level of microbiological quality required for LVP drug products. This review was first limited to specific, individual manufacturing or container-closure problems. In 1973, the review expanded to include extensive sampling of LVP products, comprehensive facility inspections, and detailed discussions between the industry and FDA (3).

Milestone. 30 Years of Pharmaceutical Technology

In March 1973, another outbreak of LVP-attributed septicemia occurred, this time associated with a different manufacturer and a different product (5% dextrose in lactated ringers or D5LR). A hospital in Milwaukee reported three cases of septicemia that developed within three hours from the start of infusion. Hospital officials suspected that each 1-L bottle of D5LR used was intrinsically contaminated. One patient died as a consequence of their intravenous therapy, and another fell critically ill. Later, CDC learned of two additional cases of septicemia caused by contaminated D5LR, one at another Wisconsin hospital and one in Ohio. The manufacturer recalled more than six lots of contaminated product. The recalled infusion was prepared by a newly modified process which included exposure of the bottles to increased pressure during the autoclave cycle (4). Concerned with the ongoing problems in the LVP industry, FDA issued a draft proposal in February 1974 that defined requirements and specifications for LVP manufacturing and processing. This was followed with the publication of a draft section to the Code of Federal Regulations, Part 212, "Current Good Manufacturing Practice in the Manufacture, Processing, Packing, or Holding of Large Volume Parenterals for Human Use," on June 1, 1976. This was the first time FDA had issued well-defined process standards for drug products, and although these standards had been discussed with industry in advance, many manufacturers objected to the limitations now being placed on LVP manufacturing and the obstacles to innovation (3). Consequently, the draft LVP regulations and proposed regulations for small-volume parenterals were withdrawn by the agency, although many of the concepts, particularly validation, were voluntarily applied by industry nonetheless.
So began the start and evolution of validation practices and technologies to the seemingly complex set of rules and guidelines used by industry today. Publications of the late 1970s and early 1980s, particularly those of the Parenteral Drug Association (PDA), introduced the concept of qualification and validation to the industry at large. Companies began to qualify and validate their sterilization processes initially, and then applied these same validation principles to other systems. With FDA's 1987 Guideline on General Principles of Process Validation, the validation of equipment, systems and processes became widespread and mandatory as manufacturers of all drug types were alerted to FDA's expectations for process validation (5). One example of this validation process is the qualification and validation of heating, ventilating, and air conditioning (HVAC), which is universal in the industry. The importance of HVAC to product quality and safety cannot be minimized. This important concept was not lost on FDA, which should be evident for anyone who reads these dated but insightful regulations.
HVAC system qualification and validation
The procedures for HVAC validation are now commonly understood. HVAC system validation is always based on design. Engineers and owners design systems, and validation specialists interpret these designs and reduce this information in the form of protocols. Quality assurance professionals and regulatory authorities review the designs at various stages of development to ensure compliance with GMP regulations and appropriate industry standards (7).
The standard sequence for HVAC system validation is installation (IQ), operational (OQ), and performance qualification (PQ). To ensure regulatory compliance, design review begins when drawings and specifications are approximately 35% complete, but always before long lead-time equipment is ordered from vendors (7). Rarely are serious errors or omissions noted during review of HVAC designs, because design criteria are understood by reputable engineers and engineering companies designing these systems.
In nearly all pharmaceutical facilities, multiple air handlers exist, each designed to support a specific zone within the building. Each zone is exhausted by one or more exhaust fans interlocked with the air-handling unit (AHU), and depending on design, return fans also. IQ and OQ protocol boundaries should be set that encompass one AHU and the interlocked return and exhaust fans only. HVAC zones do not operate in isolation but are influenced and controlled by conditions in adjacent zones. This is an important consideration when confirming room pressurizations and air-flow directions during OQ.